There has been much interest in the potential connection between mitochondrial dysfunction and insulin resistance. In our studies to identify novel regulators of mitochondrial biogenesis and function, we have found that Wnt activation in cultured muscle cells induces mitochondrial proliferation and enhances insulin sensitivity, in part through the induction of the adaptor protein insulin receptor substrate-1 (IRS-1). While the Wnt signaling network has been studied primarily in the contexts of cell proliferation, differentiation, and developmental processes, an emerging body of evidence now implicates Wnt signaling in metabolism. In particular, a strong association between allelic variations in Wnt pathway genes and the susceptibility to type 2 diabetes has been documented. We now seek to evaluate the possibility that a functional loss of Wnt signaling can produce insulin resistance in muscle cells. In Aim 1, we will use Wnt antagonists to assess the effect of inhibiting Wnt signaling on mitochondrial physiology and insulin sensitivity in muscle, using both cell culture and animal models. In Aim 2, we will examine the functional interactions between the non-canonical and the canonical Wnt signaling pathways in the context of mitochondrial physiology and insulin sensitivity in muscle. Both cell culture and animal models will be utilized. We also plan to identify the downstream targets of these two pathways by gene expression profiling and ChIP-on-chip experiments. These studies will allow us to more clearly define the role of Wnt signaling in cellular and systemic metabolism, and may lead to results with a direct bearing on the pathogenesis of human type 2 diabetes. A directed manipulation of Wnt signaling in key tissues may potentially translate into therapeutic interventions for type 2 diabetes.